Peptic ulcers, once thought to result from stress, excess acidity, or a reduction of the mucosal defense factors in the stomach, are now in a majority of cases considered to be the result of bacterial infection by Helicobacter pylori (H. pylori). The involvement of H. pylori in peptic ulcers is well documented in “Helicobacter pylori in Peptic Ulceration and Gastritis”, edited by Barry J. Marshall, Richard W. McCallum and Richard L. Guerraut, Blackwell Scientific Publications, Boston, U.S.A. The effect of treatment of H. pylori infections on long-term recurrence of gastric or duodenal ulcer is described by David Y. Graham et al. In Annals of Internal Medicine 1992; 116: No. 9.
H. pylori resides within the mucous layer of the human gastric mucosa. Due to extremely low pH, the stomach is a hostile environment to most other microorganisms. The ability of H. pylori to flourish in the stomach has been attributed to protective mechanisms such as the production of urease, protecting the bacterium from gastric acidity by creating a basic microenvironment [Taylor D. N. and Blaser M. J., Epidemiol Rev (1991) 13:42-59].
Presently, the main therapies employed in the treatment of chronic active gastritis and peptic ulcer diseases include agents for reducing the stomach acidity for example the histamine H2-receptor antagonists which result in the suppression of acid and pepsin secretion, and proton pump inhibitors which act by inhibition of the parietal cell H+/K+ ATPase, responsible for acid secretion from these cells. Proton pump inhibitors (PPIs) e.g. omeprazole and its pharmaceutically acceptable salts are disclosed for example in EP 124495. U.S. Pat. No. 5,093,342 disclosed that omeprazole may be used also as an effective anti-bacterial agent.
Other therapies for H. pylori infections include bismuth compounds and antibiotics. However, currently used treatment modalities are problematic, since post-treatment relapse rates are rising. In addition, several of these therapies are accompanied by significant side effects. For example, effective antibiotic treatment of H. pylori infections requires treatment over an extended duration (1-2 weeks) and may result in the induction of diarrhea and intestinal discomfort. The bismuth compounds are also known to have a number of significant undesirable side effects.
Current antibiotic treatment for H. pylori infections usually consists of combinations of two antibiotic agents together with an adjunctive agent, which is usually either a PPI or H2 blockers. Antibiotic resistance of H. pylori is increasing in prevalence [Hazell, SL, Eur J Clin Infect Dis (1999) 18:83-86]. Triple therapy regimen (Tetracycline, in combination with metronidazole and tripotassium dicitratobismuthate (TDB) has been found to be more effective than mono-therapy, but patient compliance and drug resistance further limits its applicability.
U.S. Pat. No. 5,196,205 (corresponding to patent application WO 89/03219) describes a method for the treatment of H. pylori infections, consisting of the administration of a bismuth compound, an antibiotic belonging to the groups of penicillins and tetracycline, and a second antibiotic, such as metronidazole. The relevant therapy thus consists of the administration of three medications (one for each active principle) several times a day.
There are also other patents and patent applications describing single or multiple therapies for the eradication of H. pylori, such as U.S. Pat. Nos. 5,472,695, 5,560,912, 5,582,837, WO 92/11848 and WO 96/02237. None of these patents and patent applications overcome the problem of the interaction between active principles in a simple and efficient manner.
It has been previously shown by one of the present inventors that the human hormone gastrin serves as a growth factor for the bacterium (Chowers et al., 1999, Gastroenterology 1999 117(5):1113-8). This observation led to the finding that gastrin analogues, particularly the gastrin molecule C-terminal such as pentagastrin (PG), inhibit the growth enhancing effect of gastrin on H. pylori, and can thus be used in the eradication of this bacterium (WO 99/65513).
According to the present art, PG is typically used as a diagnostic agent for evaluation of gastric acid secretory function. PG is prone to pepsin degradation in the stomach, therefore PG is considered inactive when administered orally. Indeed, no effect on acid secretion was noted in four normal subjects subjected to oral administration of PG, whereas some effect was noted in three additional patients with gastrointestinal abnormalities (Morrell & Keynes Lancet. 1975 Oct. 11; 2(7937):712). These findings suggested that the absorption of PG occurred through the injured duodenal mucosa, whereas there was no absorption from the stomach. In fact, this study was cited in a pharmacology textbook as a proof for lack of oral absorption of PG (Martindale Thirty-second edition, p1616, the Chapter: “Supplementary Drugs and Other Substances”). Furthermore, in vitro studies in which a bullfrog model was used, suggested that PG did not affect the gastric mucosa when applied to the luminal surface (Ayalon A. et al., 1981 The Am. J. Surg. 141:94-97).
WO 01/22985 describes the use of systemic PG in conjunction with a PPI to inhibit gastric acid secretion or as a diuretic. According to this publication, the combined administration of PG and a PPI increases the efficacy of the PPI in reducing/mitigating excess gastric acid secretion. This publication mentions that the combined PG/PPI protocol may be used in the treatment of H. pylori infections by enhancing the bioavailability of antibiotics used to treat H. pylori infection. It is neither disclosed nor suggested in WO 01/22985 that PG may be active in the stomach when administered orally.
The development of effective treatment for Helicobacter sp infections such as H. pylori infections would fulfill a long felt need. None of the prior art publications suggest or disclose that PG administered orally in combination with a PPI is effective in treating H. pylori-associated disorders.